Minutes

ITEM 1: APOLOGIES FOR ABSENCE

2. Apologies for absence were received from Professor G Williams, Mrs K Cameron (DEFRA) and Mr A Browning (VMD).

Announcements

3. On behalf of the COC the chairman congratulated Professor Peter Farmer on his appointment as the new Chair of the COM.

4. The Chairman welcomed Professor Henrik MØller as an observer, who would be acting as an adviser during the period of 2 meetings when Professor Forman will be unavailable (due to a 6-month sabbatical in Australia).

5. The Chairman also welcomed Professor Paul Elliot and Dr Jane Key from Imperial College who would be attending for item 6, and members of the DH Toxicology Unit at Imperial College attending for items 5 and 9.

6. Members were reminded of the need to make any relevant declarations of interest before discussion of items.

ITEM 2: MINUTES OF THE MEETING ON 28 JUNE 2001 (CC/MIN/2001/2)

7. The minutes were agreed subject to minor editorial changes.

ITEM 3: MATTERS ARISING

3.1 Joint meeting of COT/COC/COM

8. Members were informed that a report on the joint COT/COC/COM symposium on proteomics and genomics held at Skipton House on the 8th October 2001 would be sent to all speakers in December for comment.

9. This meeting demonstrated a useful example of closer working between the COT/COC/COM and resulted in some general advice to Government Departments and Regulatory Agencies on the value of genomics/proteomics. This would be mainly in mechanistic screening studies, rather than any routine use in chemical risk assessment

3.2 Chloropropanols

10. The Food Standards Agency (FSA) representative told the committee that applications for research had been invited for in-vivo genotoxicity tests on 1,3-dichloropropan-2-ol and 2,3-dichloropropan-1-ol (using the approach set out in the COM guidance). The closing date for submission of proposals had passed, and the FSA hoped to commission micronucleus tests with these compounds in the near future. If either proved negative, a further in-vivo test in a second tissue would be commissioned.

3.3 Dioxins

11. The FSA representative also reported that the COT statement on dioxins had recently been published on the internet and that the conclusions reached by COT were consistent with those reported in the recent published opinion of the EU Scientific Committee for Food.

3.4 ILSI/HESI research on Alternative Cancer Tests

12. Members were informed that a draft COC statement on the International Life Sciences Institute and Health and Environmental Sciences Institute (ILSI/HESI) research programme on alternative cancer tests had been sent to the ILSI/HESI Alternatives to Carcinogenicity Testing (ACT) committee.

13. The COC comments had been based on the draft documents submitted to COC in June 2001. Since then, papers and proceedings from the November 2000 workshop on alternative cancer tests have been published as a supplement to Toxicologic Pathology 2001 (Volume 29, supplement, pp1-351) and a review of the programme has been published in the journal Toxicological Sciences. A number of changes had been made to the test data (e.g. incorporation of new results for some of the test systems) and to the subsequent conclusions drawn, which members would have to consider before finalising the COC statement.

14. The committee agreed that selected members would review the COC statement in light of the recently published version of the ILSI/HESI report. To help the committee the secretariat would write to members highlighting the changes to the previous reports. It was suggested that there were a number of overview publications on the ILSI/HESI report (e.g. Dr S Cohen) and these would be useful to members.

15. The revised draft COC statement would be circulated to members for comment and then submitted to the ACT steering committee before its meeting on 10 January 2002. After considering any response from ACT, it was anticipated that the COC statement would be published shortly after the March 2002 meeting.

ITEM 4: INCREASE IN MORTALITY RATES FROM INTRAHEPATIC CHOLANGIOCARCINOMA IN ENGLAND AND WALES 1968-1998: DRAFT COC STATEMENT (CC/01/21)

16. At the previous meeting, the Committee had seen a published paper by Taylor-Robinson et al reporting an increase in mortality rate in England and Wales from 1979 to 1998 but had been made aware of a correction to a figure in the paper reporting age-specific mortality rates. The Committee had asked the secretariat to write to the authors to ask about their current interpretation of the data in view of the revised figure. The authors had replied that they did not believe that there was a need to revise their earlier interpretation and their reply was available for consideration. A further paper had also been published which reported an increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the US (Patel T, Hepatology, 33(6), pp 1353-1357). The Committee was asked to consider this further information and to finalise its statement on this issue.

17. The Committee considered that the paper by Patel showed a similar rise in reported mortality rates for intrahepatic cholangiocarcinoma to that reported for England and Wales. However, members considered that the discussion in the paper of the possible contribution of diagnostic misclassification and detection bias to the reported increase was limited. Members noted that the paper indicated that there had been a steady decrease in deaths from intrahepatic biliary tract malignancies, which paralleled the increase in deaths from extrahepatic cholangiocarcinoma but, as in the paper by Taylor-Robinson et al, the increase in the latter outweighed the decrease in the former. The Committee confirmed that there were three known risk factors for intrahepatic cholangiocarcinoma: liver flukes, Thorotrast, and primary sclerosing cholangitis. The Committee also confirmed its view that the fact that the greatest increase in intrahepatic cholangiocarcinoma had been seen in the oldest age group was consistent with diagnostic transfer, since the diagnosis in this particular age group was now more rigorous than in the past.

18. The Committee agreed that a revised statement should be circulated by post and agreed by Chairman's action.

ITEM 5: GENOTYPE-ENVIRONMENT INTERACTIONS ON RISK OF CANCER: 1st DRAFT STATEMENT (CC/01/23)

19. The Committee discussed an overview paper from the DH Toxicology Unit at the July 2000 meeting. It was agreed at this meeting that there was a need for advice on the available information on genetic polymorphisms associated with specific cancers and on the significance, if any, for public health regarding exposures to environmental chemicals. Members suggested three main areas for possible further work, which were considered at the March 2001 COC meeting. Papers were prepared by the DH Toxicology Unit at Imperial College, and covered the following topics:

i) Criteria for the design of gene-environment epidemiology studies

ii) A review of potential target genes for susceptibility to carcinogenesis

iii) A review of how gene-environment studies should be used in risk assessment process

During the discussion of paper iii on Risk Assessment Members asked for some additional work to be undertaken to develop a set of criteria for assessing whether a causal relationship existed between a particular genotype-environment interaction in respect of cancer induction. A paper considered at the June 2001 COC meeting outlined a hypothetical approach. Members considered that strength and consistency of association would be the most important factors to consider in evaluating the significance of any gene-environment interaction in the induction of a particular cancer. Members considered data on biological plausibility would be important supporting information. The 1st draft statement was appended as Annex 1 to CC/01/23.

20. The Chairman asked members to comment on the general approach taken and then to consider the first draft statement in detail.

21. Members welcomed the opportunity to see a first draft and commented on the complexity of the subject under discussion. It was agreed that a "lay" summary and glossary were essential to help make the COC conclusions understandable to a wide audience.

22. The Committee considered the Bradford-Hill criteria provided a reasonable framework for considering an assessment of a genotype-environment interaction and occurrence of cancer and acknowledged the need for a consideration of biological plausibility as part of a balanced view of all the data. Members agreed large amounts of data generated through gene discovery investigations could lead to the generation of hypotheses with little or no biological supporting data and thus it would be necessary to consider biological plausibility as part of the assessment of causality. However, it was important not to be restricted by the absence of full mechanistic data linking a genotype-environment interaction to the occurrence of cancer.

23. Members felt there needed to be a clear explanation of what was meant by the investigation of genotype-environment interactions, in particular to clarify whether additive or multiplicative models were being considered. Members agreed that a reference to the range of potential designs and the potential use of case-case designs should be included in the statement.

24. The Committee commented that lodging a hypothesis with a third party before undertaking a study was a desirable and innovative idea but commented that there would be practical difficulties in undertaking such a recommendation. It was agreed that it should be left open to investigators as to how to comply with such a suggestion.

25. Members agreed it would be necessary to reach a clear conclusion on causality between a genotype-environment interaction and occurrence of cancer before any quantitative assessment of impact for public health was undertaken. Members considered that the examples chosen in the risk assessment section were appropriate but there was a need for more thought on the model calculations and how these were derived. It was agreed that members with expertise in epidemiology should review these data in more detail before the next meeting in March 2002. The Committee felt it was inappropriate to attempt to define public health significance in terms of numbers of cases of cancer attributable to a particular genotype-environment interaction. It was noted that risk assessment would be on a case-by-case assessment depending on the strength of interaction between genotype and environment, genotype prevalence, and background rate of cancer incidence in the exposed population. Members commented that the statement did not currently refer to the potential for multiple genotype-environment interactions in the occurrence of cancer. Members suggested that it would be desirable to explain the difficulties of investigating potential multiple genotype-environment interactions in the occurrence of cancer in the statement.

26. The Committee considered that the supporting DH Toxicology Unit papers should be published on the COC Internet site to assist in the interpretation of the COC statement. Members suggested a number of minor amendments to the statement and noted the following sections of the statement needed further detailed consideration.

i) Provision of a lay summary and glossary.

ii) Further clarification of the relationship between phenotype and genotype.

iii) A definition of "causal genotype-environment interaction"

iv) Further information on nature of interactions v. Additional information on study designs and tabulation of data on numbers of case-controls required in studies.

vi) Additional information and tabulation of categories of genes which might be studies including examples.

vii) Redraft section on assessment of causality.

viii) Redraft risk assessment section. Reconsider model calculations and description of public health significance.

ix) Redraft section on potential uses in screening to remove comparison of environmental chemicals with diet/smoking.

27. The Committee agreed that considerable progress had been made and agreed that a small subgroup including epidemiological members, DH Toxicology Unit and Secretariat should be tasked with further consideration of the topics raised by members. A second draft statement would be considered at the March 2002 meeting.

ITEM 6: ALCOHOL AND BREAST CANCER: PRESENTATION OF INITIAL RESULTS OF META-ANALYSIS (CC/01/28)

28. The minutes of this item will be published when the research has been published.

ITEM 7: T25: RECENT DEVELOPMENTS AND OVERVIEW OF ECETOC WORKSHOP ON PROPOSED USES IN CHEMICAL CARCINOGEN REGULATION (CC/01/22)

29. The COC had considered the use of the T25 to estimate carcinogenic potency in 1995. It had commented that the T25 was a relatively crude estimate of potency and should be used with caution in the ranking of chemical carcinogens. It also confirmed that potency indices can be used as part of the information required to rank genotoxic chemical carcinogens, for which there was a common mechanism of action which was relevant to humans, but that they were not appropriate in the ranking of non-genotoxic carcinogens, for which there were a range of mechanisms, some of which may not be relevant to humans. At that time, the Committee concluded that the TD50 was still the most practical quantitative estimate of carcinogenic potency available for ranking genotoxic carcinogens.

30. Since 1995 there had been several new developments. A paper by Dybing et al (Pharmacology and Toxicology 80, pp 272-279) had found a good correlation between the T25 and the TD50 for a number of animal carcinogens. Within the EU, the T25 was being used as a measure of potency for use in the classification and labelling of carcinogens and to derive values for concentration limits of carcinogens in preparations. A proposal had also been put forward by some EU Competent Authorities to use the T25 in quantitative risk assessment (QRA) of non-threshold carcinogens, in the context of the ongoing assessments of existing chemicals. Finally, an ECETOC workshop had been held in November 2000 to carry out a scientific analysis of the proposed uses of the T25 in chemical carcinogen regulation and an overview of this workshop was available. The Committee was asked for its view on the T25 in the light of these developments.

31. It was noted that the ECETOC workshop had agreed that a QRA approach using the T25 gave similar results to one using the TD50, LD10 or LMS approach but that this was because all were consistently based on linear extrapolation, which was largely dependent on the top dose used in the animal bioassay. Rather than supporting the use of the T25 in QRA, this probably emphasised that all methods were flawed in a similar way. The derivation of a single risk estimate also implied a level of accuracy, which did not exist. The workshop had been content with the use of the T25 to derive concentration limits for chemicals classified as carcinogens, but not for its use in quantitative risk assessment. Interestingly, there had been support at the workshop for the view that the risk assessment of genotoxic and non-genotoxic carcinogens should be harmonised, using a threshold approach for all carcinogens.

32. The COC considered that the use of the T25 in potency ranking of genotoxic carcinogens was an acceptable pragmatic approach but that the parameter should not be overinterpreted. Ranking of genotoxic carcinogens was of value in prioritisation of chemicals for risk evaluation. It was noted that there should be no pressure to rank non-genotoxic carcinogens because tolerable exposure levels could be derived using an approach based on knowledge of mechanism, identification of no adverse effect level, and use of uncertainty factors. The use of T25 to rank genotoxic carcinogens for carcinogenic potency, and to aid in the Classification, Packaging and Labelling of carcinogens as considered acceptable.

33. The Committee deferred a discussion of the use of the T25 in QRA in view of the forthcoming review of the COC guidelines.

ITEM 8: THE MINIMUM DURATION OF CARCINOGENICITY STUDIES IN RATS (CC/01/25)

34. Members were aware that the life span of some strains of rat used in carcinogenicity studies had declined and had lead to compromised credibility of negative results at termination at 24 months, since the current test guidelines specify that at least half the group given the top dose should survive for 24 months.

35. One option for solving this problem of declining rat life-spans might be to reduce the duration of the study. The COC had previously discussed other options such as avoiding the use of strains known to have shorter life-spans (e.g. Charles-River and Sprague-Dawley).

36. Several published papers have considered the effects of reducing rat carcinogenicity studies from 24 to 18 months. Two of these studies, considered by the committee, reached contradicting conclusions. Davies et al (Food and Chemical Toxicology, vol 38, 2000, 219-235) examined whether the 'power' of the rat carcinogenicity study to detect potential carcinogens would be lost if the study was reduced to 18 months, and concluded it would not. Kodell et al (Toxicological Sciences, vol 55, 2000, 415-432) conducted a review and concluded that statistical power would be lost if studies were terminated at 18 or 21 months. Monte Carlo modelling of tumorigenesis was used by Kodell et al to demonstrate inadequate statistical power of studies terminated at 18 or 21 months. Therefore, the authors concluded significant human carcinogens might be overlooked if studies were terminated at 18 months.

37. The committee agreed that some rat strains such as Wistar, and Sprague-Dawley (in certain labs) have adequate survival at 24 months. Members noted the argument put forward by Davis et al that the pathology associated with old age might mask important cancer pathology in animals terminated at 24 months. Davis et al had also argued that it is possible that an earlier onset of the incidence of a common spontaneous tumour type could be detected at 18 months and missed at 24 months. However, members considered that in 24-month studies, autopsy of the dead animals and analysis of tumour incidence in decedents would pick this up.

38. The committee agreed that a single study would not be looked at in isolation and that consideration of the mechanism of an effect was crucial in the overall evaluation. Members were also concerned about modifying an already imperfect lifetime model, and agreed that possible dietary methods of extending life span, such as by caloric restriction, needed to be considered on a case-by-case basis with regard to laboratory historical control data on tumour incidence.

39 The committee did not agree with the conclusions drawn by Davis et al that carcinogens detected after 18 months were unlikely to be relevant to humans. Members were concerned that such shortened studies might not be sufficiently sensitive to detect some human carcinogens.

40. The COC concluded that there was insufficient evidence to recommend a change to the international OECD guidelines, that for a negative result to be acceptable in a rat carcinogenicity bioassay, survival should be at least 50% in all groups. It was the responsibility of the study director to use rat strains that would ensure adequate survival at 24 months.

41. The secretariat would redraft conclusions to paper CC/01/25 and circulate by post for comment.

ITEM 9: RISK ASSESSMENT: REVIEW OF COC GUIDELINES DISCUSSION OF SCOPE OF REVIEW (CC/01/24).

42. The COC published guidelines for the testing of chemicals for carcinogenicity in 1982. These were influential in establishing internationally agreed methods. In 1991 the committee published revised guidelines for the evaluation of chemicals for carcinogenicity which provided advice on identification of genotoxic and non-genotoxic carcinogens, the conduct and evaluation of animal bioassays, evaluation of epidemiology studies, and methods of risk assessment. The document was particularly influential with regard to approaches used for risk assessment of genotoxic and non-genotoxic carcinogens.453. Since 1991 there has been considerable developments in the understanding of cancer and the evaluation of data from both animal and epidemiology studies.

44. It was now a suitable time for the COC to reconsider its guidelines. The objective of the current draft proposal paper is to update the COC guidelines. It was suggested that the COC take a similar approach as to that adopted by the COM, and focus at least in the first instance, on key areas of risk assessment of carcinogens (i.e. chapter 7 of the old 1991 guidelines). The intention is to publish a comprehensive view on carcinogenic risk assessment. It is proposed that this should include up to date advice on the most appropriate procedures for carcinogen risk assessment, advantages and limitations of approaches in current use, and research and development that would improve the approach to carcinogenic risk assessment.

45. Assessors from other Government Departments/Regulatory agencies were asked for suggestions on topics for inclusion in the review. Suggestions included, clear statement on invalid use of dose-response analysis of animal tumour data, uncertainty factors for non-genotoxic carcinogens, comparative risk assessments for genotoxic carcinogens, the As Low As Reasonably Practical (ALARP) policy, and developing "Index doses" for genotoxic carcinogens. Members were asked to initially focus on the review on risk assessment, and to consider other generic topics separately.

46. Members agreed with the proposed topics but suggested that later consideration could be given to other important issues. The committee suggested that the use of surrogate endpoints for carcinogenicity, such as DNA adducts as markers, and the protection of vulnerable sub populations such as children, the elderly and the sick were important issues that should be dealt with in separate reviews.

47. Members agreed that a pragmatic approach needed to be developed for the risk assessment of genotoxic carcinogens. This could include consideration of the concept of minimum risk levels. It was agreed that good mechanistic arguments would be required to adopt a threshold approach to the risk assessment of specific genotoxic carcinogens. This would have to be on a chemical-by-chemical basis, and possible mechanistic examples might include interference with mitotic spindle structures or rapid detoxication.

48. It was agreed that the Department of Health's Toxicology Unit should be asked to prepare a review paper which would be used to initiate discussion on the update of COC advice on risk assessment of chemical carcinogens.

ITEM 10: COMMITTEE PROCEDURES IN THE LIGHT OF PHILLIPS ENQUIRY (CC/01/26)

49. The report of the BSE Enquiry published in October 2000 included a number of findings relating to the role of scientific advisory committees and the Government's assessment and use of scientific advice. The Government's interim response to the Enquiry's report - issued in February 2001 was put out for public consultation (9 February to 30 April 2001).

50. The current paper (CC/01/26) had previously been submitted to the COT for discussion on 16 October 2001. This paper outlines points made in the Government's final response to the BSE Enquiry report and incorporates views expressed during the consultation exercise. This paper was presented to the COC for information and comment, and members were invited to consider whether the committee needed to change its mode of working.

51. The committee commented on a number of areas highlighted as being important by the report. Members agreed that procedures for horizon scanning were in place for generic issues relating to cancer risk assessment. Identifying cancer 'scares' was far more problematic. On seeking wider consultation and scientific views outside of the mainstream, members considered that they would consult in respect of important generic documents, but acknowledged that this could be difficult. Such an approach would require exercising discretion where appropriate and on a case by case basis.

52. The committee agreed that openness could be increased by making more background papers available on the internet (after clearance by members), which would be useful in supporting detailed statements already available. Joint meetings on general areas of interest to the COC/COT/COM, which would be open to the public, could be held once every year or 18 months, such as the recent symposium on genomics and proteomics. It was felt that COC statements were detailed and acknowledged areas of difficulty and uncertainty.

53. Members considered that when required, quick ad hoc advice was already sought. This might involve obtaining advice from the chairman and/or members by post/e-mail, and may involve the setting up of working groups and additional extraordinary meetings if necessary. The committee agreed that contingency planning was not applicable to the COC, as it was not involved in risk management.

54. The COC agreed that improving communications of its advice to the public was difficult because of its specialist and very technical nature. Members were informed that to help improve communication, a 'what's new' section had been placed on the COC website. It was considered that glossaries and lay summaries could help with public understanding. However, this was acknowledged to be a very resource intensive area for the secretariat to take forward.

55. Members agreed that it would be useful to have an item each year where members suggested areas/topics that needed further consideration in the light of new evidence.

ITEM 11: PAPERS FOR INFORMATION (CC/01/27)

56. The paper, Exploring the relation of alcohol consumption to risk of breast cancer by Ellison et al, American Journal of Epidemiology, vol 154, (8), 740-747, was made available to members for information, and was circulated under item 6.

ITEM 12: ANY OTHER BUSINESS

57. Members suggested that the SHASU study on landfill sites and cancer incidence that had recently been published should be made available to the committee for information.

ITEM 13: DATE OF NEXT MEETING

58. 7 March 2002

ACTIONS

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